Dopamine is a neurotransmitter in the brain. Since this discovery, made in the 1950's, the function of dopamine in the brain has been intensely explored. To date, it is well established that dopamine is essential in several aspects of brain function including motor, cognitive, sensory, emotional and autonomous functions (e.g. regulation of appetite, body temperature, sleep). Thus, modulation of dopaminergic function may be beneficial in the treatment of a wide range of disorders affecting brain functions. In fact, drugs that act, directly or indirectly at central dopamine receptors are commonly used in the treatment of neurological and psychiatric disorders, e.g. Huntington and Parkinson's disease and schizophrenia.
Antipsychotic drugs (or neuroleptics) are a class of compounds with diverse effects on different receptor systems. However, they have in common the ability to block dopamine D2 receptors in the basal ganglia (i.e. striatum) and are used to manage psychosis (including delusions or hallucinations, as well as disordered thought), particularly in schizophrenia and bipolar disorder.
The cerebral cortex encompasses several major regions that are involved in higher functions such as thought, feelings, memory and planning. Biogenic amines such as dopamine are important for mammalian cortical function. The ascending dopamine pathways innervate the cortex. Primary or secondary dysfunctions in the activity of these pathways lead to dysregulation of the activity at dopamine in these brain areas and subsequently to manifestations of psychiatric and neurological symptoms. Both dopamine D1 and N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex play a critical role in synaptic plasticity, memory mechanisms, and cognition.
Huntington's disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by progressive deterioration of motor and cognitive functions as well as behavioural and psychiatric disturbances. It is well established that certain aspect of dopaminergic functions are also affected in Huntington's disease. Neuropathological changes in Huntington's disease involve prominent cell loss and atrophy in the striatum but also in many other brain regions such as the cortex, substantia nigra, hypothalamus, cerebellum and thalamus.
In HD, glutamate and dopamine (DA) transmission is altered, which is likely to induce an imbalance in activity of the direct and indirect pathways and to contribute to the motor, cognitive, and psychiatric symptoms of HD (i.e. communication between the cortex and striatum, Capeda et al; ASN Neuro 2010 2 (2) e00033). Therefore, compounds which can strengthen the cortical dopamine and NMDA transmission, and exert antagonism of excessive subcortical dopamine transmission, can balance aberrant functioning in the cortico-striato-thalamic network controlling motor functions (Alexander et al; Ann. Rev. Neurosci. 1986 9 357-381).
JP 2006-193494 (Dainippon Ink and Chemicals, Inc) describes certain quaternary ammonium compounds useful as therapeutic agent for heart diseases.
WO 2009/133107 (NSAB, Filial af NeuroSearch Sweden AB, Sverige) describes certain 1-(2,3-dihydro-1,4-benzodioxin-2-yl)methanamine derivatives, WO 2009/133109 (NSAB, Filial af NeuroSearch Sweden AB, Sverige) describes certain 1-(2,3-dihydro-1,4-benzodioxin-2-yl)methanamine derivatives, and WO 2009/133110 (NSAB, Filial af NeuroSearch Sweden AB, Sverige) describes certain 1-(4H-1,3-benzodioxin-2-yl)methanamine derivatives, useful as modulators of dopamine neurotransmission, and more specifically as dopaminergic stabilizers. However, the phenoxy-ethyl-amine derivatives of the present invention have not previously been reported.